The emerging role of chromatin remodelers in neurodevelopmental disorders: a developmental perspective

Abstract

Neurodevelopmental disorders (NDDs), including intellectual disability (ID) and autism spectrum disorders (ASD), are a large group of disorders in which early insults during brain development result in a wide and heterogeneous spectrum of clinical diagnoses. Mutations in genes coding for chromatin remodelers are overrepresented in NDD cohorts, pointing towards epigenetics as a convergent pathogenic pathway between these disorders. In this review we detail the role of NDD-associated chromatin remodelers during the developmental continuum of progenitor expansion, differentiation, cell-type specification, migration and maturation. We discuss how defects in chromatin remodelling during these early developmental time points compound over time and result in impaired brain circuit establishment. In particular, we focus on their role in the three largest cell populations: glutamatergic neurons, GABAergic neurons, and glia cells. An in-depth understanding of the spatiotemporal role of chromatin remodelers during neurodevelopment can contribute to the identification of molecular targets for treatment strategies.

Analysis of a Set of KDM5C Regulatory Genes Mutated in Neurodevelopmental Disorders Identifies Temporal Coexpression Brain Signatures

“…These genes show a peculiar coexpression pattern in hippocampal and neocortical regions, with two intersected cardinal areas involved in flexible cognition and social behavior [ 48 ]. Moreover, three of them— KDM5C , ARX , and PHF8 —show high expression levels at the timing of neuronal proliferation with a decrease during neuronal migration and synaptogenesis—two highly vulnerable processes underpinning neural circuit development [ 2 ]. By contrast, ZNF711 shows an oscillatory trend with a very low expression level during the proliferation phase that increases, reaching a peak at the beginning of neuronal migration and synaptogenesis ( Figure 7 A).…”

“…Brain development and neuronal differentiation are complex processes involving spatio-temporal changes in chromatin remodeling and transcriptional activity in specific brain regions and neural cell types [ 1 , 2 , 3 ]. Alterations in regulatory genes of chromatin remodeling and transcription factors (TFs) cause a huge spectrum of neurodevelopmental disorders (NDDs) [ 2 , 4 , 5 , 6 ].…”

“…Brain development and neuronal differentiation are complex processes involving spatio-temporal changes in chromatin remodeling and transcriptional activity in specific brain regions and neural cell types [ 1 , 2 , 3 ]. Alterations in regulatory genes of chromatin remodeling and transcription factors (TFs) cause a huge spectrum of neurodevelopmental disorders (NDDs) [ 2 , 4 , 5 , 6 ]. We recently uncovered genetic and functional relationships within a set of X-linked NDD genes formed by the epigenetic eraser Lysine-Specific Demethylase 5C ( KDM5C ; MIM:314690) and its upstream regulators, Aristaless-related homeobox ( ARX ; MIM:300382), PHD Finger protein 8 ( PHF8 ; MIM:300560) and Zinc Finger protein 711 ( ZNF711 ; MIM:314990) [ 4 , 5 ].…”

Chromatin Remodeling in the Brain-a NuRDevelopmental Odyssey

“…Each disorder is rare, with only ~30 to 50 individuals diagnosed to date in each case. These syndromes are designated as “NuRDopathies” due to their overall similarity (reviewed in [ 58 , 59 ]). They are also designated as overgrowth and intellectual disability (OGID) syndromes, as afflicted individuals typically present with ID and macrocephaly [ 60 , 61 , 62 , 63 , 64 , 65 ].…”

A Randomized Controlled Trial of Intranasal Oxytocin in Phelan-McDermid Syndrome

“…Read Full License Introduction Gene discovery approaches, followed by functional analysis using model systems, have clari ed the neurobiology of several genetic subtypes of autism spectrum disorder (ASD) and led to important opportunities for developing novel therapeutics (Javed et al, 2020;Mossink et al, 2020;Varghese et al, 2017;Harony-Nicolas et al, 2015). ASD is now understood to have multiple distinct genetic risk loci and one example is SHANK3, where haploinsu ciency through deletion or sequence variants causes Phelan-McDermid syndrome (PMS), which is characterized by global developmental delay, motor skills de cits, delayed or absent speech, and ASD (Soorya et al, 2013).…”